This Program Project Grant application seeks support for clinical and experimental studies concerning the major obstacles to successful allogeneic and autologous stem cell transplantation for the treatment of hematologic malignancies. These problems include recurrence of the underlying disease, graft-versus-host disease and infectious with cytomegalovirus. The program consists of two clinical and four experimental projects that are supported by six cores. The two clinical projects propose studies designed to eradicate leukemia and lymphoma utilization innovations in the preparatory regimen as well as in the treatment of minimal residual disease following either allogeneic and lymphoma antigens in the preparatory regimen of patients undergoing allogeneic for leukemia and myelodysplasia or autologous transplantation for lymphoma. It is also the goal of our studies to use antigen-specific cytolytic T cells in the treatment of minimal residual disease in patients undergoing autologous transplantation for B cell lymphoma and allogeneic transport for Ph+ ALL. Two transplant studies involve genetic manipulation of hematopoietic cells to convey resistance to HIV in patients with HIV-related lymphoma utilizing adeno-associated virus and lentiviruses. Studies will also continue on the prevention of graft-versus- host disease and will develop novel immunologic strategies to prevent cytomegalovirus disease after allogeneic transplantation. The two clinical projects in allogeneic and autologous transplantation serve as a resource for the experimental projects in the program. The four experimental projects address biologically important questions related to transplantation including acquisition of immunity to CMV, the development of antigen-specific cytolytic T cells, treatment of minimal residual disease after autologous and allogeneic transplantation, and genetic modification of stem cells to induce HIV resistant immune reconstitution. These projects attempt to bring laboratory based innovative concepts to clinical use in the treatment of Administration for the coordination of research, Biostatistics, Cellular and Molecular Correlative studies, radioimmunotherapy, Long-Term Follow-Up and a new Biomedicine Production Facility for the production of antibodies, antigen specific cells and viral vectors to be used in the experimental studies proposed in this grant.